As disclosed in U.K. Pat. No. 2 065 655 A (Upjohn) and in U.S. Pat. No. 4,266,069 (Walker), it is known that certain flurbiprofen-type intermediates can be prepared by coupling aminohalobenzenes, such as 4-bromo-2-fluoroaniline, diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate, etc., with benzene compounds. The coupling techniques taught by Upjohn and Walker include reaction of the arylamines and benzene compounds in the presence of water, an inorganic nitrite, and a strong acid--a process which, when applied to the coupling of a 2-(4-amino-3-fluorobenzene)propionitrile with benzene, has been found to result in low yields of biaryl compound.
Copending application Ser. Nos. 488,192 now U.S. Pat. No. 4,482,502 (Ramachandran) and 488,068 (Ramachandran I), both filed Apr. 25, 1983, teach that it has been found difficult to obtain high yields of biaryl compound when arylamines bearing one or more acid-sensitive ar-substituents, e.g., cyanoalkyl, carboxyalkyl, and alkylcarboxyalkyl groups, have been coupled with benzene compounds. As revealed by Ramachandran and Ramachandran I, this has presented problems when it has been desired to prepare flurbiprofen intermediates from aminohalobenzenes such as 2-(4-amino-3-fluorobenzene)propionitrile and alkyl 2-(4-amino-3-fluorobenzene)propionates; and they have solved these problems by using copper/strong acid catalyst systems and/or temperature control in aryl coupling processes utilizing alkyl nitrites.
Although it has been found that the processes of Ramachandran and Ramachandran I can be employed quite advantageously in the preparation of biaryl compounds from difficulty-coupled arylamines, as well as from arylamines that are more easily coupled, it would be desirable to find an alternative process which would not require the use of costly and hazardous alkyl nitrites.
Rosenberg et al., "Conversion of Arenediazonium Tetrafluoroborates into Unsymmetrical Biaryls Using Catalysts Other than Polyethers," Tetrahedron Letters, Vol. 21, pp. 4141-4144 (1980), teach that arenediazonium salts can be coupled with benzene in the presence of potassium acetate and various phase-transfer catalysts, including long-chain alkali metal carboxylates.